1. Field of the Invention
The invention relates to analgesic 5,9-methanocycloocta[b]pyridin-2(1H)-one derivatives, their preparation, and use as analgesic agents.
2. Description of the Related Art
Pain is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals experience pain by various daily hurts and aches, and occasionally through more serious injuries or illnesses. For example, pain may be caused by neurothlipsis or nervous lesions due to the expansion of cancer cells in cancer patients, by damage of human tissues or organs, by autoimmune reaction such as inflammation (arthritis, gastritis, or hepatitis), or by abnormities in the central nervous system (brain tissues).
Pain of any type is the most frequent reason for physician consultation in the United States, prompting over half of all Americans to seek medical care annually and causing heavy economic losses to society. Pain management is one of the most common means of symptomatic treatments, and virtually the only focus in late stages of terminal illnesses, such as incurable cancer.
Conventional analgesics include two main types: opiate receptor ligands, with the typical example of morphine, which has strong analgesic effects but is prone to cause addiction; and non-narcotic analgesics, with the typical example of aspirin-derived paracetamol. With multiple mechanisms of action and conceived and manufactured successfully via modern processes of drug design, screening and development, this type of drugs have weak analgesic effects, but they seldom forming dependence. Although some of these analgesics have other serious side effects, e.g., they may cause damage to the digestive tract, they are widely used and have an estimated combined market share of nearly 10 billion US dollars.
Acetylcholine was the first neurotransmitter to be discovered. However, there has been hardly any research in the area of acetylcholine receptors (AcChR) and acetylcholinesterase as analgesic targets. Nevertheless, in European Pat. No. EP 413667 A and U.S. Pat. No. 5,010,083, compounds used for treatment of both memory loss and relief of pain have been reported, which suggests that improvement of memory has some association with analgesia, and further reveals that increase in the level of acetylcholine may have analgesic action.
In addition, Stoyan once reported that the alkaloids nivalin and syntostigmine could alleviate migraine pain (Stoyan, Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie, 1968, 102, pp. 299-312). It was later found that these two compounds could inhibit the activity of acetylcholine esterase. Because of a low inhibition activity of acetylcholine esterase or a low ability to permeate the blood-brain barrier, higher doses of these two compounds, and other acetylcholine esterase inhibitors subsequently tested, are required in order to provide therapeutic effects.
To achieve high concentrations, these compounds must be administered by injection. Hence, on one hand, the blood drug concentration is so high so as to have many side effects; on the other hand, the administration by injection is inconvenient. As a result, the research on acetylcholine esterase inhibitors used for treatment of migraine was put on hold. This was the first time when it was proposed that acetylcholine esterase inhibitors could be used for treatment of migraine.
The breakthrough in this field came from research and development of novel inhibitors of acetylcholine esterase. These novel inhibitors, such as donepezil, have high activity, highly-selectivity and high permeability through the blood-brain barrier, so that they are able to overcome the shortcomings of the first generation of acetylcholine esterase inhibitors described above for the treatment of migraine. As disclosed in U.S. Pat. No. 6,608,088, donepezil was observed to have efficacy on migraine in clinical trials.
Huperzine A can inhibit acetylcholine esterase (ACHE) selectively, has high activity, and is easy to penetrate blood-brain-barrier and spinal-fluid-barrier. In addition huperzine A has effects on improvement of memory reappearance and enhancement of memory retention. Recently, we have found that Huperzine A and derivatives thereof have strong analgesic effects (Chinese Pat. Appl. 200510014685.6), and curative effect on migraine. However, Huperzine A has certain drawbacks, such as high toxicity, low therapeutic index (TI), narrow window between maximum tolerance dose and curative dose (CD).